RESUMO
Transforming growth factor ß (TGF-ß)/Smad3 plays a vital role in hypertensive cardiac fibrosis. The long non-coding RNA (lncRNA) Erbb4-IR is a novel Smad3-dependent lncRNA that mediates kidney fibrosis. However, the role of Erbb4-IR in hypertensive heart disease remains unexplored and was investigated in the present study by ultrasound-microbubble-mediated silencing of cardiac Erbb4-IR in hypertensive mice induced by angiotensin II. We found that chronic angiotensin II infusion induced hypertension and upregulated cardiac Erbb4-IR, which was associated with cardiac dysfunction, including a decrease in left ventricle ejection fraction (LVEF) and LV fractional shortening (LVFS) and an increase in LV mass. Knockdown of cardiac Erbb4-IR by Erbb4-IR short hairpin RNA (shRNA) gene transfer effectively improved the angiotensin II-induced deterioration of cardiac function, although blood pressure was not altered. Furthermore, silencing cardiac Erbb4-IR also inhibited angiotensin II-induced progressive cardiac fibrosis, as evidenced by reduced collagen I and III, alpha-smooth muscle actin (α-SMA), and fibronectin accumulation. Mechanistically, improved hypertensive cardiac injury by specifically silencing cardiac Erbb4-IR was associated with increased myocardial Smad7 and miR-29b, revealing that Erbb4-IR may target Smad7 and miR-29b to mediate angiotensin II-induced hypertensive cardiac fibrosis. In conclusion, Erbb4-IR is pathogenic in angiotensin II (Ang II)-induced cardiac remodeling, and targeting Erbb4-IR may be a novel therapy for hypertensive cardiovascular diseases.
RESUMO
Objective: To evaluate the effectiveness and safety of Linggui Zhugan decoction (LZD) as an adjunct treatment of premature contraction in patients with coronary heart disease. Methods: PubMed, Embase, Web of Science, ClinicalTrials.gov Cochrane Library, Chinese Knowledge Infrastructure, Wanfang database, Sino Med, and VIP database were searched from inception until July 2022. Two reviewers independently selected randomized controlled trials assessing the effectiveness of LZD combined with conventional antiarrhythmic drugs in treating premature contraction in patients with coronary heart disease compared to conventional antiarrhythmic drugs only. The clinical effectiveness was considered as the primary outcome, and the times of premature junctional beats in 24 h after treatment along with adverse reactions were considered secondary outcomes. The Cochrane risk of bias 2 tool was used for the risk of bias assessment. Meta-analysis was conducted using RevMan 5.4.1. and RStudio software. Results: A total of 14 studies including 1,236 participants were included. The primary outcome indicated that, compared with antiarrhythmic drugs alone (especially ß receptor blockers), the combination of LZD and conventional antiarrhythmic drugs resulted in higher clinical effectiveness (RR = 1.29, 95% CI: [1.22,1.36]) and lower number of premature junctional beats in 24 h (MD = -71.14, 95% CI: [-76.23, -66.06]) at end-of-intervention. The differences in adverse reactions (RR = 0.42, 95%CI: [0.15, 1.14], p = 0.09) were not significant. The risk of bias was marginally high among the studies. Funnel plot and Harbord's test (t = 1.63, p = 0.1346) indicated no existence of publication bias. Conclusion: The current evidence shows that LZD can increase the effectiveness of conventional antiarrhythmic drugs for treating premature contraction in patients with coronary heart disease. However, the results should be interpreted with caution because of the high overall risk of bias. Future studies with appropriate randomization and double-blind methods are warranted to confirm these findings. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=296628], identifier [CRD42022296628].
RESUMO
Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis and chronic heart failure. Although TGF-ß/Smad3 signalling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db/db mice. At the age of 32 weeks, Smad3WT-db/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO-db/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3 ± db/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2-mediated ubiquitin proteasome degradation, thereby inducing IBα to suppress NF-kB-driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3-dependent miRNAs by up-regulating cardiac miR-29b while suppressing miR-21 to exhibit the cardioprotective effect on Smad3KO-db/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.
